Monogenic variants in CDC45-MCM-GINS (CMG) replisome proteins can cause human natural killer cell deficiency (NKD) by making proliferative NK cell progenitors sensitive to replication stress induced by replication fork stalling. While several monogenic inherited variants in this complex have been described, family members with the same inherited variants often have variable clinical and cellular phenotypes. Here, we used iPSCs from two siblings with the same hereditary compound heterozygous GINS4 variants but variable disease expressivity. Cell cycle impairment and increased apoptosis were detected in NK cells from patient-derived iPSCs following NK cell lineage commitment but not in pluripotent cells. While this effect was detected in cell lines from both siblings, the efficiency of NK cell differentiation was variable and correlated with differential clinical severity of NKD. Further investigation of allelic expression of inherited GINS4 variants demonstrated equal biallelic expression of GINS4 in pluripotent cells and primary CD34⁺ progenitors. However, allelic bias in lineage committed NK cells led to over- or under-representation of more damaging inherited GINS4 heterozygous variants that tracked with differential cellular and clinical severity. This study identifies allelic bias as an epigenetic factor that contributes to the phenotypic variations of monogenic diseases and further defines the etiology of NK cell-lineage specific immunodeficiency arising from CMG variants.